EDITORIALS
Stem cell factor: the bridge between bone marrow adipocytes and hematopoietic cells
Ziru Li and Ormond A. MacDougald
Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
E-mail: ZIRU LI - liziru@umich.edu
doi:10.3324/haematol.2019.224188
W
hite adipocytes serve as an energy reservoir to
store excessive calories in the form of lipid
droplets and protect other tissues or organs from
ectopic lipid accumulation. Brown adipocytes express
uncoupling protein 1 and are integral to adaptive thermoge-
nesis. Whereas the functions of adipocytes in either white or
brown adipose tissues are well documented, our knowledge
of bone marrow adipocytes (BMA) remains in its infancy.
Bone marrow adipose tissue (BMAT) occupies approximate-
ly 50-70% of the bone marrow volume in human adults.1 It
is a dynamic tissue and responds to multiple metabolic con-
ditions. For example, BMAT increases with obesity, aging,
diabetes, caloric restriction, and irradiation.2 Although the
significance of BMAT expansion under these conditions is
still largely unknown, BMA interact locally with hematopoi-
etic and bone cells, and contribute to global metabolism
through secretion of adiponectin, leptin, stem cell factor
(SCF), and other functional factors. For example, A-ZIP/F1
mice, which lack adipose tissues throughout the body,
including BMAT, have delayed hematopoietic regeneration
in long bones after irradiation.3 Our latest work also
observed that depletion of BMA by bariatric surgery is asso-
ciated with a decrease in bone marrow erythroid cells and
anemia.4 The importance of BMA and the derived factors on
hematopoiesis is further enhanced by a study in this issue of
the Journal, in which Zhang et al.5 demonstrate that BMAT-
derived SCF mediates metabolic regulation of
hematopoiesis.
Stem cell factor, also known as Kit ligand (Kitl), is a
hematopoietic cytokine expressed in fibroblasts and
endothelial cells, as well as in BMA.3 Together with its recep-
tor, c-Kit, SCF plays important roles in the maintenance of
hematopoietic stem cells (HSC) and hematopoiesis.
Blockade of the interaction between c-Kit and SCF with anti-
c-Kit antibody promotes the clearance of HSC, which indi-
cates the importance of Kitl/c-Kit signaling in HSC self-
renewal.6 Loss-of-function mutations in c-Kit cause macro-
cytic anemia, or even embryonic lethality under some severe
mutations.7 Inversely, mice with c-Kit gain-of-function
mutations developed erythrocytosis compatible with myelo-
proliferative disorders.8 Analyses of multiple cell populations
isolated from bone marrow and adipose tissue have demon-
strated that BMA and LepR-positive (+) stromal cells are the
primary sources of SCF, which is required for the regenera-
tion of HSC and hematopoiesis after irradiation.3 Zhang et al.
report that BMA-derived SCF is important for hematopoietic
homeostasis under basal (Figure 1), obese and aging condi-
tions, and in response to β3-adrenergic agonists.5
Knockout of SCF in adipocytes with an adiponectin driver
does not influence circulating SCF concentrations or pheno-
types of the peripheral adipose depots, which is perhaps due
to compensatory expression of SCF from other sources, such
as endothelial cells, fibroblasts and stromal cells.
Interestingly, Zhang et al. observed a significant loss of SCF
haematologica | 2019; 104(9)
in the bone marrow supernatant, which indicates that
BMAT is a primary source of SCF in bone marrow.5
Deficiency of SCF in BMAT reduces the bone marrow cellu-
larity, hematopoietic stem and progenitor cells (HSPC), com-
mon myeloid progenitors (CMP), megakaryocyte-erythro-
cyte progenitor (MEP) and granulocyte-monocyte progeni-
tors (GMP) under steady-state condition. Consistent with
these changes in the progenitor cells of bone marrow, mice
deficient for adipocyte SCF develop macrocytic anemia and
reduction of neutrophils, monocytes and lymphocytes in cir-
culation. In contrast to results in this study, Zhou et al.
reported that the conditional deficiency of SCF in adipocytes
driven by adiponectin-Cre/ER had no effect on
hematopoiesis under basal conditions.3 Although further
investigation is necessary, the discrepancy between these
two studies might be due to the time-frame of SCF deletion,
tamoxifen injection and/or animal lines. Of note, the dele-
tion of SCF has no effect on the proliferation of HSPC evi-
denced by colony-forming assays, which suggests that
defects in BMAT-derived SCF influences the bone marrow
microenvironment rather than the intrinsic function of
HSPC.
Since adiponectin-Cre is expressed in both peripheral
adipocytes and BMA, it is possible that there might be
effects on hematopoiesis that are independent of BMAT. To
more specifically study effects of BMA on the bone marrow
niche and hematopoiesis, Zhang et al. also deleted the Kitl
using osterix promoter, which traces BMA but not the other
adipocytes. Again, knockout of Kitl from the osterix-positive
(+) cells reduced bone marrow cellularity, hematopoietic pro-
genitor populations and mature blood cells including red
blood cells (RBC), neutrophils and monocytes, which is con-
sistent with the phenotypes from mice lacking adipocytic
Kitl. Of note, in addition to BMA, osterix+ progenitors also
trace to osteoblasts.9,10 Mesenchymal and osteoblast lineage
cells are involved in the maintenance and regulation of the
supportive microenvironments necessary for quiescence,
self-renewal and differentiation of HSC.11,12 However, the
SCF from osteoblasts is not required for HSC maintenance in
adult bone marrow under steady-state conditions.13
Although the possible effects of SCF derived from osterix+
progenitors on hematopoiesis could not be excluded and the
bone phenotypes were not explored in this mouse model, it
should be appreciated that authors used both adiponectin-
and osterix-driven Cre enzyme to confirm the phenotypes of
SCF-deficiency on hematopoiesis. These results strongly
point to BMA as an important source of SCF since the com-
mon cell type traced by adiponectin and osterix drivers is the
BMA; however, development of BMA-specific transgenic
mouse tools will be required to truly confirm these observa-
tions of BMA and the roles of SCF in the bone marrow niche
homeostasis and hematopoiesis.
The authors also investigated whether BMA-derived SCF
is required for hematopoietic adaptation to aging or high fat
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 Editorials

Figure 1. Bone marrow adipocytes influence the maintenance of hematopoietic stem cell (HSC) and hematopoiesis. Bone marrow cellularity is complex, but is main-
ly composed of hematopoietic cells and bone marrow adipocytes (BMA), which appear after birth and accumulate with age, obesity and irradiation. BMA originate
from osterix-positive (+) progenitor cells and secret adiponectin, stem cell factor (SCF) and other functional factors. In this study, Zhang et al.5 have demonstrated that
BMAT-derived SCF plays important roles in HSC maintenance and hematopoietic differentiation under baseline, aging and obese conditions. Deficiency of SCF in
BMAT hinders the self-renewal of HSC by influencing the bone marrow microenvironment and hematopoiesis through unknown mechanisms. RBC: red blood cell;
MPP: multipotent progenitor; CMP: common myeloid progenitor; MEP: megakaryocyte-erythrocyte progenitor; GMP: granulocyte-monocyte progenitor; CLP: common
lymphoid progenitor.

diet (HFD)-induced obesity. Whereas HFD, per se, did not
increase the SCF concentrations in bone marrow super-
natant, this treatment increased bone marrow cellularity,
HSPC, and mature blood cells, including granulocytes,
monocytes and lymphocytes, the effects of which were
eliminated by SCF deficiency in adipocytes. Aging causes
similar increases in the HSPC, especially in the myeloid
lineage populations, and most of these effects required
adipocyte-derived SCF. Further, these investigators
explored a potential role for SCF in mediating effects of a
β3-adrenergic receptor agonist. Activation of these recep-
tors induces the lipolysis of white adipocytes, and while
although BMAT lipolysis is relatively resistant to β-adren-
ergic signaling,14 Zhang et al. observed that after adminis-
tration of a β3-adrenoceptor agonist, CL316, 243, SCF
expression was increased in bone marrow without signif-
icant changes in the BMA numbers.5 Consistent with the
elevated SCF in bone marrow, the numbers of HSPC,
including Lin-Sca1+c-Kit+ (LSK) cell, multipotent progeni-
tor (MPP), MEP, GMP and CLP were increased by CL316,
243 injection, the effects of which were compromised by
adipocyte-specific deficiency of SCF. Based on the animal
models described above, it should be noted that alter-
ations of BMAT, SCF and hematopoiesis were not tightly
associated under these conditions, which suggests that
hematopoietic metabolism is regulated by factors beyond
BMAT and its derived SCF. The global effects of obesity,
aging and β3-adrenoceptor activation cannot be excluded
from this scenario. In addition, other secreted factors
from BMAT may also play significant roles in
hematopoiesis under these conditions. Unfortunately, the
secretome of BMAT remains largely unexplored.
In summary, Zhang et al.5 have extended our under-
standing of the roles of BMAT in the bone marrow niche
and the interaction between BMA and hematopoietic
cells. They thoroughly addressed their hypotheses using a
variety of animal models and complete profiling of
hematopoietic changes. However, due to the complexity
of whole-body metabolism and the lack of BMA-specific
transgenic tools, further work will be required to deter-
mine whether BMA-derived SCF regulates hematopoiesis
directly through Kitl/c-Kit signaling in hematopoietic cells
or indirectly by changing the microenvironment of the
bone marrow niche.

1690 haematologica | 2019; 104(9)


Acknowledgments
This work was supported by grants from the NIH to OAM
(R24 DK092759; R01 DK62876), and from the American
Diabetes Association to ZL (1-18-PDF-087).
References
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2. Li Z, Hardij J, Bagchi DP, Scheller EL, MacDougald OA.
Development, regulation, metabolism and function of bone marrow
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3. Zhou BO, Yu H, Yue R, et al. Bone marrow adipocytes promote the
regeneration of stem cells and haematopoiesis by secreting SCF. Nat
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4. Li Z, Hardij J, Evers SS, et al. G-CSF partially mediates effects of
sleeve gastrectomy on the bone marrow niche. J Clin Invest.
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New potential players in hepcidin regulation
Maxwell Chappell and Stefano Rivella
Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Cell and Molecular Biology Graduate Group,
University of Pennsylvania, Abramson Research Center, Philadelphia, PA, USA
E-mail: STEFANO RIVELLA - rivellas@email.chop.edu
doi:10.3324/haematol.2019.224311
T
he manuscript by Liu and colleagues, published in
this issue of Haematologica, reports the identifica-
tion of novel compounds able to increase hepcidin
expression in normal mice as well as in animals affected
by hemochromatosis and β-thalassemia intermedia (or
non-transfusion-dependent thalassemia) (Figure 1A).1
Hepcidin is the master regulator of iron secreted from
the liver and acts on ferroportin, a transmembrane pro-
tein that functions as an iron exporter.2,3 Once hepcidin
binds ferroportin, the complex is rapidly degraded, pre-
venting iron egress.2,3 Ferroportin is expressed in many
types of cells, including enterocytes and macrophages.2,3
Therefore, the relative abundance of hepcidin in the cir-
culation and ferroportin on cell membranes control iron
absorption (from enterocytes) and iron recycling (from
macrophages).2,3
Hepcidin expression is regulated by iron, inflammation
and erythropoiesis.2,3 With regard to iron-mediated control
of hepcidin, this is achieved through at least two mecha-
nisms. The first senses the amount of intracellular iron in
liver sinusoidal endothelial cells and responds by synthesiz-
ing BMP6, and other similar ligands, belonging to the
TGFβ-like family.2-4 Increased intracellular concentration of
iron leads to secretion of BMP6 from these cells.2-4 As a con-
sequence, BMP6 binds and activates receptors that trigger
phosphorylation of a SMAD complex and stimulate hep-
cidin expression in hepatic cells.2-4
The second mechanism senses the iron in circulation
by recognizing iron-loaded transferrin molecules.3
haematologica | 2019; 104(9)
Editorials
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Genes Dev. 1989;3(6):816-826.
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perivascular cells maintain haematopoietic stem cells. Nature.
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ergic stimulation. Bone. 2019;118:32-41.
Molecules such as HFE, transferrin receptor-2, and others
communicate intracellularly when the transferrin satura-
tion levels increase.3 It has been hypothesized that this
sensing complex potentiates the SMAD complex activat-
ed by BMP6.5 Alternatively, or in addition, it has been
suggested that this complex acts upon hepcidin expres-
sion by decreasing the ERK1/2 pathway.10
Under conditions that require enhanced red cell pro-
duction (as a consequence of a transient or chronic ane-
mia), hepcidin synthesis is normally suppressed.2 A few
factors have been identified that could play a role in this
mechanism, such as erythroferrone and platelet-derived
growth factor BB.7,8 In particular, erythroferrone is secret-
ed by erythroid cells and acts as a trap ligand, limiting the
activity of BMP6 and other similar molecules.9
Another player in the regulation of hepcidin is the mol-
ecule matriptase-2 (or TMPRSS6).2,3 This molecule pre-
vents hepcidin overexpression, which could lead to
hypoferremia and anemia.3,10 Although it is unclear which
pathways and molecules control TMPRSS6, it has been
shown that TMPRSS6 is required for erythropoietin-
mediated hepcidin suppression in mice.11,12
In primary forms of hemochromatosis, patients show
excessive iron absorption and suffer from iron overload
(Figure 1A).7,8 This happens when hepcidin, or other
genes that control its expression, are mutated.2,3 In sec-
ondary forms of hemochromatosis (as in β-thalassemia),
the anemia triggers increased iron absorption, likely by
increased expression of erythroferrone and other hypox-
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